Live from AAPS Biotech: Large Molecules Mimic Small Molecule Development

A theme shared by several of Wednesday’s sessions at the AAPS National Biotechnology Conference seems to be how the tools and techniques that have evolved for development of small molecules are spilling over into the design of large molecules.

Dr. Michael Hall from Amgen presented a talk in which he described the tools and techniques used to evaluate the catabolism and in vivo stability of a peptide-antibody fusion construct. The analysis revealed a site prone to degradation, and the protein was subsequently reengineered to be more stable. Dr. Ho Cho of Ambrx presented data on antibody drug conjugates made using the company’s platform technology whereby the site of conjugation of the toxin to the antibody can be precisely controlled. He showed data demonstrating that moving the site of conjugation affects the biophysical properties, retention time, formation of high molecular weight species, and thermal stability of the antibody drug conjugate. Moreover, he said that for at least 20 antibody drug conjugates, moving the site of conjugation affects pharmacokinetics and pharmacodynamics. What I found striking about the two talks was that developers were doing what amounted to structure-activity relationship analysis, the bread-and-butter of small molecule development. Can protein libraries be far behind?